Congenital erythropoietic porphyria (CEP) and congenital erythropoietic protoporphyria are rare hereditary diseases of cattle, dogs, cats, and other species. Clinical signs of CEP include photosensitization; red-brown discoloration of teeth (erythrodontia), bones, and other tissues; and anemia. Unlike CEP in other species, bovine CEP does not manifest with brown teeth; affected animals commonly display neurological signs as well as photosensitization. Selective breeding can be used to lessen disease incidence by decreasing the use of genetic carrier animals for breeding purposes.
Congenital erythropoietic porphyria (CEP) and congenital erythropoietic protoporphyria (CEPP) affect cattle, dogs, cats, pigs, horses, pygmy hedgehogs, foxes, and humans. In all cases, due to enzyme deficiencies, porphyrins build up in various tissues, causing clinical signs mainly related to photosensitization and, less often, to bone, neurological, and organ abnormalities.
Congenital Erythropoietic Porphyria in Animals
CEP results from a substantial decrease in uroporphyrinogen III synthase (URO-synthase) activity. With decreased URO-synthase activity, hydroxymethylbilane accumulates, primarily in erythrocytes and their precursors, and is nonenzymatically converted to uroporphyrinogen I. Further decarboxylation of uroporphyrinogen I leads to the formation of various porphyrinogen I isomers.
Porphyrinogen I isomers are pathogenic when they accumulate in large amounts and are oxidized to their corresponding porphyrins. Accumulation of porphyrinogen isomers within bone marrow erythroid precursors results in cell damage and hemolysis.
Porphyrin I isomers are also released into circulation and deposited in skin, bone, and other tissues. Cutaneous photosensitivity occurs because porphyrins deposited in skin are photocatalytic and cytotoxic. Presumably, exposure of skin to sunlight (and other sources of long-wave ultraviolet light) leads to phototoxic excitation of isomers, formation of oxygen radicals, and subsequent tissue and vessel damage. Urinary porphyrin excretion is greatly increased (100–1,000 times normal).
CEP was first reported in South African Shorthorn cattle; however, most cases have since been reported in the Holstein breed. CEP is usually confined to herds in which inbreeding or close line breeding is practiced. The disease has been recognized in the US, Canada, Denmark, Jamaica, England, South Africa, Australia, and Argentina. This broad geographic distribution suggests that CEP likely is found worldwide and probably affects all meat-producing animals, especially cattle, swine, and sheep.
Porphyria in swine is rare and incompletely described. Affected pigs have discolored teeth and excessive uroporphyrin in urine. In contrast to CEP-affected cattle and humans, affected swine are not anemic and do not develop clinical signs of photosensitization. The specific genetic defect in swine is unknown; therefore, its relevance to CEP in other animals is also unknown. Nonetheless, the disorder is inherited as an autosomal dominant trait.
A feline model similar to human CEP due to deficient URO-synthase activity has been identified by characteristic clinical phenotype and confirmed by biochemical and molecular genetic studies (1). In this case, sequencing the cat’s URO-synthase gene revealed two homozygous, missense mutations in exons 3 and 6. This synergistic interaction of two rare amino acid substitutions in the URO-synthase polypeptide resulted in the feline model of human CEP.
Historically, cats that developed brownish discolored teeth that fluoresced pink under UV light, along with increased URO and coproporphyrinogen concentrations, were believed to have CEP. The disease was also thought to be inherited as an autosomal dominant trait (as in some pig models), whereas in humans and cattle, the disease is inherited as an autosomal recessive trait. However, cats with the CEP-like phenotype and autosomal dominant inheritance actually have feline acute intermittent porphyria (AIP) and not CEP. Cats with AIP do not display the same abdominal and neurological signs as humans, and erythrodontia is common in cats but rare in humans.
Clinical Signs of Congenital Erythropoietic Porphyria
Photosensitization
Red/brown discoloration of tissues
Anemia
Animals with CEP develop sensitivity to sunlight due to porphyrin accumulation, especially in areas with thin or less-protected skin. Ulcers, lesions, and scarring can develop on exposed skin. In severe cases, affected skin may darken and harden. Prolonged exposure to sunlight causes typical lesions of photosensitization including hyperemia, vesicle formation, and superficial necrosis of unpigmented portions of skin. Skin lesions' severity depends on the intensity of solar radiation and the extent of cutaneous pigmentation found in specific animal families. Some animals become progressively unthrifty unless protected from sunlight.
Because of porphyrin buildup in RBCs, affected animals’ teeth (especially deciduous teeth), bones, and even urine may appear reddish-brown or fluorescent pink under ultraviolet light. This distinctive coloration is often one of the first clinical signs noticed by owners or veterinarians. Heterozygous animals seem to be normal; however, homozygous recessive animals are affected at birth with lifelong reddish-brown discoloration in teeth, bones, and urine. Excess coproporphyrin I and uroporphyrin I in urine color it amber or reddish-brown.
Abnormal RBCs are more fragile than normal RBCs, leading to hemolysis and, over time, chronic hemolytic anemia. Anemia can cause fatigue, weakness, and increased heart rate as the animal’s body compensates for decreased oxygen transport.
Normochromic hemolytic anemia develops, with macrocytes and microcytes and marked basophilic stippling. Splenomegaly eventually develops as the spleen works extra hard to trap and remove damaged RBCs from the circulation.
Diagnosis of Congenital Erythropoietic Porphyria
Diagnosis should be based on the following:
excretion of abnormal uroporphyrins
brown discoloration of teeth (which fluoresce when irradiated with ultraviolet light)
discolored urine
hemolytic anemia
The recessive genetic character is widely distributed in cattle, but clinical signs are comparatively rare. Clinically normal heterozygotes have lower levels of URO-synthase than do normal animals; however, laboratory identification of the carrier state is impractical and not widely used because of the low incidence of disease. Morbidity can be controlled by keeping affected animals indoors and out of direct sunlight.
Selective breeding practices can help prevent CEP in animals by ensuring that carrier animals are not bred together.
Bovine Congenital Erythropoietic Protoporphyria
Erythropoietic protoporphyria was first reported in humans in 1961 and in cattle in the US in 1977. The disease has since been reported in cattle in Ireland, the UK, Australia, France, and New Zealand. Bovine congenital erythropoietic protoporphyria (BCEPP) is an inherited condition; it is most commonly reported in Limousin cattle but has also been described in the Blonde d'Aquitaine breed.
BCEPP is caused by a deficiency in ferrochelatase activity. This enzyme is involved in the final stage of the 8-step heme biosynthesis pathway, catalyzing the chelation of ferrous iron to protoporphyrin in heme production. Excess protoporphyrin is lipophilic and accumulates in cellular membranes. The molecule absorbs light in a range of wavelengths, and energy absorbed from this light can be transferred to oxygen, resulting in a reactive oxygen species that may interact with proteins, lipids, or DNA (2).
Clinical Signs of BCEPP
BCEPP is thought to be inherited in an autosomal recessive pattern. Photosensitization is the prevailing clinical presentation and results in the formation of reactive oxygen species, but neurological signs may also be present in cattle (see image of dermatitis, calf). This phenomenon appears to be associated with the bovine form and not the human form of the disease.
Courtesy of Dr. Eoin G. Ryan.
Neurological signs with BCEPP primarily present as intermittent seizures upon exposure to sunlight; if cattle are housed, seizures and neurological signs (eg, ataxia) occur less commonly. (See the video of a Limousin heifer with ataxia.)
Clinical signs of photosensitization are similar to those seen with other causes of primary and hepatogenous photosensitization; however, characteristic clinical signs such as pink teeth and anemia, which are indicative of CEP, are absent.
Diagnosis of BCEPP
Photosensitization, seizures, or ataxia
Fecal testing
Biochemical analysis
Diagnosis of BCEPP should be based on clinical signs of photosensitization, seizures, or ataxia in primarily Limousin or Limousin crossbred calves or juveniles with no apparent exposure to plants containing photodynamic agents (primary photosensitization). Fecal testing results should be negative for liver flukes that typically cause elevated liver enzymes. Normal liver enzymes on biochemical analysis rule out hepatogenous photosensitization, which could lead to skin lesions and neurological signs (hepatic encephalopathy).
An EDTA blood sample can be submitted to a porphyria laboratory for testing using fluorescence emission spectroscopy; positive results show a prominent porphyrin peak. With genomic DNA isolation from a positive EDTA blood sample, affected animals are expected to be homozygous for an autosomal recessive mutation in the ferrochelatase gene, a mutation that causes the obliteration of the stop codon in the gene and consequent extension of the transcript, leading to loss of enzyme function.
After a diagnosis of BCEPP, bulls should be carefully selected for breeding to decrease the risk of future cases.
Protoporphyria in Other Species
CEPP has also been described in other species, including dogs, which differ particularly with respect to liver involvement.
A case of CEPP and protoporphyric hepatopathy was described in a 6-month-old Clumber Spaniel with clinical signs of small stature, recurrent dermatitis on the head, and progressive pigmentary hepatopathy (3). Clinicopathological findings included nonanemic hypochromic microcytosis, hypocholesterolemia, persistently high serum liver enzyme activities, and anicteric hyperbilirubinemia. Further analyses confirmed marked porphyrin accumulation in blood, urine, feces, and liver tissue; protoporphyrin accumulation in RBCs and liver tissue; and a signature porphyrin profile and fluorescence peak consistent with erythropoietic protoporphyria.
This dog was treated with ursodeoxycholic acid to decrease biliary cholesterol saturation, administered antioxidants, and kept away from sunlight. At 4 years old, the dog had no evidence of jaundice but with probable persistent erythropoietic protoporphyria–related solar dermatopathy.
Key Points
Congenital erythropoietic porphyria and congenital erythropoietic protoporphyria are rare and heritable conditions.
Protoporphyria should be considered in young Limousin cattle with clinical signs of photosensitization that cannot easily be explained or that are recurrent, especially if intermittent neurological signs occur.
Porphyrias affect all animal species, and selective breeding practices can help prevent CEP and CEPP by ensuring that carrier animals are not bred together.
For More Information
Capuzzello G, Kaczmarska A, Gutierrez-Quintana R, Jonsson NN, Viora L. A case of bovine erythropoietic protoporphyria in a female Limousin calf. Large Anim Rev. 2024;30(5):223-226.
Clavero S, Ahuja Y, Bishop DF, et al. Diagnosis of feline acute intermittent porphyria presenting with erythrodontia requires molecular analyses. Vet J. 2013;198(3):720-722.
Giddens WE, Labbe RF, Swango LJ, Padgett GA. Feline congenital erythropoietic porphyria associated with severe anemia and renal disease. Am J Pathol. 1975;80(3):367-386.
Huxley JN, Lloyd EL, Parker CS, Woolf JR, Strugnell BW. Congenital erythropoietic porphyria in a longhorn calf. Vet Rec. 2009;165(23):694-695.
Pence ME, Liggett AD. Congenital erythropoietic protoporphyria in a Limousin calf. J Am Vet Med Assoc. 2002;221(2):277-279.
Queiroz CRR, Machado M, Bromberger CR, et al. Case report: a possible case of congenital erythropoietic porphyria in a Gir calf: a clinical, pathological, and molecular approach. Front Vet Sci. 2021;8:632762.
Also see pet owner content regarding congenital erythropoietic porphyria in cats.
References
Clavero S, Ahuja Y, Bishop DF, et al. Diagnosis of feline acute intermittent porphyria presenting with erythrodontia requires molecular analyses. Vet J. 2013;198(3):720-722. doi:10.1016/j.tvjl.2013.10.008
McAloon CG, Doherty ML, O’Neill H, Badminton M, Ryan EG. Bovine congenital erythropoietic protoporphyria in a crossbred Limousin heifer in Ireland. Ir Vet J. 2015;68(1):15. doi:10.1186/s13620-015-0044-3
Kunz BC, Center SA, Randolph JF, Walker JD, Choi AE, Anderson KE. Congenital erythropoietic protoporphyria and protoporphyric hepatopathy in a dog. J Am Vet Med Assoc, 2020;257(11):1148-1156. doi:10.2460/javma.2020.257.11.1148
